This invention relates generally to novel cyclic hydroxamic acids as metalloproteinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly identified metalloproteinase enzymatic activity) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
Tumor necrosis factor (TNF) is a cell associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP""s are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-a from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechansisms are involved.
EP 0,780,286 describes MMP inhibitors of formula A: 
wherein Y can be NHOH, R1 and R2 can combine to form a cycloalkyl or heterocyclo alkyl group, R3 and R4 can be a variety of groups including H, and R5 can be substituted aryl.
WO 97/20824 depicts MMP inhibitors of formula B: 
wherein ring V contains six atoms, Z is O or S, and Ar is an aryl or heteroaryl group. Ar is preferably a monocyclic aryl group with an optional para substituent or an unsubstituted monocyclic heteroaryl group.
EP 0,818,442 illustrates MMP inhibitors of formula C: 
wherein Ar is optionally substituted phenyl or naphthyl, z can be absent and X and Y can be a variety of substituents. Compounds of this sort are not considered to be part of the present invention.
The compounds of the present invention act as inhibitors of MMPs, in particular aggrecanase and TNF. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibiton of aggrecanase, TNF-C, and other metalloproteinases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA,.
Accordingly, one object of the present invention is to provide novel cyclic hydroxamic acids which are useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel compounds of formula (I) for use in therapy.
It is another object of the present invention to provide the use of novel compounds of formula (I) for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPS, TNF, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R1, R2, and R3 are defined below, are effective metalloprotease inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94COR5, xe2x80x94CO2H, CH2CO2H, xe2x80x94CO2R6, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94NHRa, xe2x80x94N(OH)COR5, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94SONHRa, xe2x80x94SN2H2Ra, xe2x80x94PO(OH)2, and xe2x80x94PO(OH)NHRa;
ring B is a 3-8 membered non-aromatic ring with 0-1 carbonyl groups and from 0-2 ring heteroatoms selected from O, N, NR2, and S(O)p, provided that ring B contains a total of 0-1 ring S and O atoms;
R1 is xe2x80x94Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Yaxe2x80x94Za;
U is absent or is selected from: O, NRaxe2x80x2, C(O), C(O)O, OC(O), C(O)NRaxe2x80x2, NRaxe2x80x2C(O), OC(O)O, OC(O)NRaxe2x80x2, NRaxe2x80x2C(O)O, NRaxe2x80x2C(O)NRaxe2x80x2, S(O)p, S(O)pNRaxe2x80x2, NRaxe2x80x2S(O)p, and NRaxe2x80x2SO2NRaxe2x80x2;
X is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Y is absent or selected from O, NRaxe2x80x2, S(O)p, and C(O);
Z is absent or selected from a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRaxe2x80x2, C(O), C(O)O, OC(O), C(O)NRaxe2x80x2, NRaxe2x80x2C(O), OC(O)O, OC(O)NRaxe2x80x2, NRaxe2x80x2C(O)O, NRaxe2x80x2C(O)NRaxe2x80x2, S(O)p, S(O)pNRaxe2x80x2, NRaxe2x80x2S(O)p, and NRaxe2x80x2SO2NRaxe2x80x2;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Ya is absent or selected from O, NRaxe2x80x2, S(O)p, and C(O);
Za is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
provided that U, Y, Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R2 is selected from H, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRaxe2x80x2)rxe2x80x2O(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2NRa(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rC(O)(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rC(O)O(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2OC(O)(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rC(O)NRa(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2NRaC(O)(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2OC(O)O(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2OC(O)NRa(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2NRaC(O)O(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2NRaC(O)NRa(CRaRaxe2x80x2)rxe2x80x94Q (CRaRaxe2x80x2)rxe2x80x2S(O)p(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2SO2NRa(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2NRaSO2(CRaRaxe2x80x2)rxe2x80x94Q, and (CRaRaxe2x80x2)rxe2x80x2NRaSO2NRa(CRaRaxe2x80x2)rxe2x80x94Q;
Q is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rd and a 5-14 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
R3 is selected from H, C1-6 alkylene-Qxe2x80x2, C2-6 alkenylene-Qxe2x80x2, C2-6 alkynylene-Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2O(CH2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2NRa(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2NRaC(O)(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2C(O)NRa(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rC(O)(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rC(O)O(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x22)rxe2x80x2S(O)p(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, and (CRaRaxe2x80x2)rxe2x80x2SO2NRa(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2;
Qxe2x80x2 is selected from H, phenyl substituted with 0-3 Rd, naphthyl substituted with 0-3 Rd and a 5-10 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rd;
alternatively, R2 and R3 combine to form a fused benzo ring substituted with R3xe2x80x2;
R3xe2x80x2 is selected from H, (CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, C2-6 alkenylene-Qxe2x80x2, C2-6 alkynylene-Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2O(CH2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2NRa(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2NRaC(O)(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2C(O)NRa(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rC(O)(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rC(O)O(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rS(O)p(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, and (CRaRaxe2x80x2)rSO2NRa(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Raxe2x80x3, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, S(O)pRaxe2x80x3, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, S(O)pRaxe2x80x3, CF3, CF2CF3, C3-10 carbocyclic residue and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, S(O)pRaxe2x80x3, CF3, CF2CF3, C3-10 carbocyclic residue and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R5, at each occurrence, is selected from C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Rf, C3-8 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
rxe2x80x2, at each occurrence, is selected from 1, 2, 3, and 4;
provided that the moiety in ring B adjacent to CHxe2x80x94A is other than substituted or unsubstituted Nxe2x80x94SO2-phenyl-Oxe2x80x94Ar and Nxe2x80x94SO2-phenyl-Sxe2x80x94Ar, wherein Ar is aryl or heteroaryl; and,
provided that when ring B is cyclopentyl or cyclohexyl, then R1 is other than a substituted or unsubstituted phenyl-S(O)pxe2x80x94 group.
[2] In a preferred embodiment, the present invention provides a novel compound of formula II, wherein; 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from COR5, xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)COR5, xe2x80x94SH, and xe2x80x94CH2SH;
ring B is a 5-7 membered non-aromatic ring with 0-1 carbonyl groups and 0-2 ring heteroatoms selected from O and NR2, provided that ring B contains a total of 0-1 ring O atoms;
R1 is xe2x80x94Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
U is absent or is selected from: O, NRaxe2x80x2, C(O), C(O)O, C(O)NRaxe2x80x2, NRaxe2x80x2C(O), S(O)p, and S(O)pNRaxe2x80x2;
X is absent;
Y is absent;
Z is absent or selected from a C3-6 carbocyclic residue substituted with 0-5 Rb and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRaxe2x80x2, C(O), C(O)O, C(O)NRaxe2x80x2, NRaxe2x80x2C(O), S(O)p, and S(O)pNRaxe2x80x2;
Xa is absent or selected from C1-4 alkylene;
Ya is absent or selected from O and NRaxe2x80x2;
Xa is selected from H, a C3-6 carbocyclic residue substituted with 0-5 Rc and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
provided that U, Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R2 is selected from H, C1-6 alkylene-Q, (CRaRaxe2x80x2)rxe2x80x2O(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2NRa(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rC(O)(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rC(O)O(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rC(O)NRa(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rxe2x80x2S(O)p(CRaRaxe2x80x2)rxe2x80x94Q, and (CRaRaxe2x80x2)rxe2x80x2SO2NRa(CRaRaxe2x80x2)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocyclic residue substituted with 0-5 Rd, and a 5-10 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
R3 is selected from H, C1-6 alkylene-Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2O(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2NRa(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)5xe2x80x2C(O)NRa(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rC(O)(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rC(O)O(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, (CRaRaxe2x80x2)rxe2x80x2S(O)p(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2, and (CRaRaxe2x80x2)rxe2x80x2SO2NRa(CRaRaxe2x80x2)rxe2x80x94Qxe2x80x2;
Qxe2x80x2 is selected from H, phenyl substituted with 0-3 Rd, naphthyl substituted with 0-3 Rd and a 5-6 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Raxe2x80x3, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, CF3, C3-6 carbocyclic residue and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, CF3, C3-6 carbocyclic residue and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R5, at each occurrence, is selected from C1-6 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dibxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-6 alkyl substituted with 1-2 Rf, C3-6 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-6 cycloalkyl, C1-5 alkoxy, phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
rxe2x80x2, at each occurrence, is selected from 1, 2, 3, and 4;
provided that the moiety in ring B adjacent to CHxe2x80x94A is other than substituted or unsubstituted Nxe2x80x94SO2-phenyl-Oxe2x80x94Ar and Nxe2x80x94SO2-phenyl-Sxe2x80x94Ar, wherein Ar is aryl or heteroaryl; and,
provided that when ring B is cyclopentyl or cyclohexyl, then R1 is other than a substituted or unsubstituted phenyl-S(O)pxe2x80x94 group.
[3] In a more preferred embodiment, the present invention provides a novel compound of formula II, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, and xe2x80x94N(OH)COR5;
ring B is a 5-7 membered non-aromatic ring with 0-1 carbonyl groups and 0-2 ring heteroatoms selected from O and NR2, provided that ring B contains a total of 0-1 ring O atoms;
R1 is xe2x80x94Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94XaYaxe2x80x94Za;
U is absent or is selected from: O, NRaxe2x80x2, C(O), C(O)NRaxe2x80x2, S(O)p, and S(O)pNRaxe2x80x2;
X is absent;
Y is absent;
Z is absent or selected from a C5-6 carbocyclic residue substituted with 0-3 Rb and a 5-6 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRaxe2x80x2, C(O), C(O)NRaxe2x80x2, S(O)p, and S(O)pNRaxe2x80x2;
Xa is absent or selected from C1-2 alkylene;
Ya is absent or selected from O and NRaxe2x80x2;
Xa is selected from H, a C5-6 carbocyclic residue substituted with 0-3 Rc and a 5-10 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rc;
provided that U, Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R2 is selected from H, C1-6 alkylene-Q, (CRaRaxe2x80x2)rC(O)(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x2)rC(O)O(CRaRaxe2x80x2)rxe2x80x94Q, (CRaRaxe2x80x3)rC(O)NRa(CRaRaxe2x80x2)rxe2x80x94Q, and (CRaRaxe2x80x2)rxe2x80x2S(O)p(CRaRaxe2x80x2)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocyclic residue substituted with 0-3 Rd and a 5-10 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rd;
R3 is selected from H, C1-6 alkylene-Qxe2x80x2, (CHRa)rxe2x80x2O(CHRa)rxe2x80x94Qxe2x80x2, (CHRa)rxe2x80x2NRa(CHRa)rxe2x80x94Qxe2x80x2, (CHRa)rxe2x80x2C(O)NRa(CHRa)rxe2x80x94Qxe2x80x2, (CHRa)rC(O)(CHRa)rxe2x80x94Qxe2x80x2, and (CHRa)rxe2x80x2S(O)p(CHRa)rxe2x80x94Qxe2x80x2;
Qxe2x80x2 is selected from H, phenyl substituted with 0-3 Rd, and a 5-6 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H and C1-4 alkyl;
Raxe2x80x3, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, and CF3;
Rc, at each occurrence, is independently selected from C16 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRaxe2x80x2, C(O)Ra, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRaxe2x80x2, C(O)Ra, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, CF3 and phenyl;
R5, at each occurrence, is selected from C1-4 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
rxe2x80x2, at each occurrence, is selected from 1, 2, 3, and 4;
provided that the moiety in ring B adjacent to CHxe2x80x94A is other than substituted or unsubstituted Nxe2x80x94SO2-phenyl-Oxe2x80x94Ar and Nxe2x80x94SO2-phenyl-Sxe2x80x94Ar, wherein Ar is aryl or heteroaryl; and,
provided that when ring B is cyclopentyl or cyclohexyl, then R1 is other than a substituted or unsubstituted phenyl-S(O)pxe2x80x94 group.
[4] In a further preferred embodiment, the present invention provides a novel compound of formula III, wherein; 
ring B is a 5-7 membered non-aromatic ring with 0-1 carbonyl groups and 0-2 ring heteroatoms selected from O and NR2, provided that ring B contains a total of 0-1 ring O atoms;
R1 is xe2x80x94Uxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
U is absent or is selected from C(O) and C(O)NRaxe2x80x2;
Z is absent or selected from phenyl substituted with 0-3 Rb and pyridyl substituted with 0-3 Rb;
Ua is absent or is O;
Xa is absent or is CH2 or CH2CH2;
Ya is absent or is O;
Za is selected from H, phenyl substituted with 0-3 Rc, pyridyl substituted with 0-3 Rc, and quinolinyl substituted with 0-3 Rc;
provided that U, Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, or Oxe2x80x94O group;
R2 is selected from H, C1-6 alkylene-Q, C(O)(CRaRaxe2x80x2)rxe2x80x94Q, C(O)O(CRaRaxe2x80x2)rxe2x80x94Q, C(O)NRa(CRaRaxe2x80x2)rxe2x80x94Q, and S(O)p(CRaRaxe2x80x2)rxe2x80x94Q;
Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-2 Rd and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;
Ra, at each occurrence, is independently selected from H and CH3, and CH2CH3;
Raxe2x80x2, at each occurrence, is independently selected from H and CH3, and CH2CH3;
Raxe2x80x3, at each occurrence, is independently selected from H and CH3, and CH2CH3;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRaxe2x80x2, C(O)Ra, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRaxe2x80x2, C(O)Ra, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, CF3 and phenyl;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3; and,
rxe2x80x2, at each occurrence, is selected from 1, 2, and 3;
provided that the moiety in ring B adjacent to CHxe2x80x94A is other than substituted or unsubstituted Nxe2x80x94SO2-phenyl-Oxe2x80x94Ar and Nxe2x80x94SO2-phenyl-Sxe2x80x94Ar, wherein Ar is aryl or heteroaryl; and,
provided that when ring B is cyclopentyl or cyclohexyl, then R1 is other than a substituted or unsubstituted phenyl-S(O)pxe2x80x94 group.
[5] In a still further preferred embodiment, the present invention provides a novel compound of formula IV: 
[6] In an even further preferred embodiment, the present invention provides a compound selected from the group:
trans-N-Hydroxy-2-[(4-phenyl-1-piperidinyl)carbonyl]cyclopentanecarboxamide;
trans-N-Hydroxy-2-{[4-[(4-methylphenoxy)methyl]-1-piperidinyl]carbonyl}cyclopentanecarboxamide;
trans-N-Hydroxy-2-[[4-(2-phenoxyethyl)-1-piperidinyl]carbonyl]cyclopentanecarboxamide;
trans-N-Hydroxy-Nxe2x80x2-[4-(phenylmethoxy)phenyl]-1,2-cyclopentanedicarboxamide;
trans-N-Hydroxy-Nxe2x80x2-[4-(4-pyridinylmethoxy)phenyl]-1,2-cyclopentanedicarboxamide;
trans-N-[4-[(3,5-Dichlorophenyl)methoxy]phenyl]-Nxe2x80x2-hydroxy-1,2-cyclopentanedicarboxamide;
trans-N-Hydroxy-Nxe2x80x2-[4-[4-quinolinyloxy)methyl]phenyl]-1,2-cyclopentanedicarboxamide;
trans-N-Hydroxy-Nxe2x80x2-[4-(4-pyridinylmethyl)phenyl]-1,2-cyclopentanedicarboxamide;
trans-N-Hydroxy-Nxe2x80x2-[4-(phenylmethoxy)phenyl]-1,2-cyclohexanedicarboxamide;
trans-N-Hydroxy-Nxe2x80x2-[4-[(4-quinolinyloxy)methyl]phenyl]-1,2-cyclohexanedicarboxamide;
trans-N-Hydroxy-Nxe2x80x2[4-[(5-quinolinyloxy)methyl]phenyl]-1,2-cyclohexanedicarboxamide;
trans-N-Hydroxy-Nxe2x80x2-[4-[(6-quinolinyloxy)methyl]phenyl]-1,2-cyclohexanedicarboxamide;
(3R-trans)-2-methylpropyl4-[(hydroxyamino)carbonyl]-3-[[[4-[(4-quinolinyloxy)methyl]phenyl]amino]carbonyl]-1-piperidinecarboxylate;
(3R-trans)-2-Methylpropyl3-[(hydroxyamino)carbonyl]-4-[[[4-[(4-quinolinyloxy)methyl]phenyl]amino]carbonyl]-1-piperidinecarboxylate;
(3R-trans)-1-(3,3-Dimethyl-1-oxobutyl)-N3-hydroxy-N4-[4-[(4-quinolinyloxy)methyl]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-N3-Hydroxy-1-[(1-phenylcyclopropyl)carbonyl]-N4-[4-[(4-quinolinyloxy)methyl]phenyl]-3,4-piperidinedicarboxamide;
17(3R-trans)-N3-Hydroxy-1-(phenylsulfonyl)-N4-[4-[(4-quinolinyloxy)methyl]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-2-Methylpropyl3-[(hydroxyamino)carbonyl]-4-[[[4-(2-phenylethoxy)phenyl]amino]carbonyl]-1-piperidinecarboxylate;
(3R-trans)-2-Methylpropyl4-[[[2-fluoro-4-(2-phenylethoxy)phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
(3R-trans)-2-Methylpropyl3-[(hydroxyamino)carbonyl]-4-[[[4-(4-pyridinyloxy)phenyl]amino]carbonyl]-1-piperidinecarboxylate;
(3R-trans)-1-(3,3-Dimethyl-1-oxobutyl)-N3-hydroxy-N4-[4-(4-quinolinyloxy)phenyl]-3,4-piperidinedicarboxamidemono;
(3R-trans)-N4-[4-[3,5-bis(Trifluoromethyl)phenoxyy]phenyl]-1-(2,2-dimethylpropyl)-N3-hydroxy-3,4-piperidinedicarboxamide;
(3R-trans)-N4-[4-(3,5-dichlorophenoxy)phenyl]-1-(2,2-dimethylpropyl)-N3-hydroxy-3,4-piperidinedicarboxamide;
(3R-trans)-N4-[4-(3-chlorophenoxy)phenyl]-1-(2,2-dimethylpropyl)-N3-hydroxy-3,4-piperidinedicarboxamide;
(3R-trans)-1-(2,2-dimethylpropyl)-N3-hydroxy-N4-(4-phenoxyphenyl)-3,4-piperidinedicarboxamide;
(3R-trans)-tert-Butyl4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
(3R-trans)-N3-Hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-Methyl4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
(3R-trans)-2-propyl4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
(3R-trans)-Cyclopropylmethyl4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
(3R-trans)-Cyclopentylmethyl4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
(3R-trans)-Allyl4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
(3R-trans)-Propargyl4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
Tetrahydro-4H-pyran-4-yl(3R-trans)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
(S)-Tetrahydrofuran-3-yl(3R-trans)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
2-Methyl-4-thiazolemethyl(3R-trans)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
2-Thiazolemethyl(3R-trans)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
4-Thiazolemethyl(3R-trans)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
4-Quinolinylmethyl(3R-trans)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]amino]carbonyl]-3-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
(3R-trans)-1-Acetyl-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-(2-Furoyl)-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-[(2-amino-4-thiazole)acetyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-[(2-pyridinyl)carbonyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-[(2-Chloro-6-methyl-4-pyridinyl)carbonyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-[(4-pyridinyl)carbonyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-[(4-quinolinyl)carbonyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-[(2-quinolinyl)carbonyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-Benzoyl-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-[(4-Methylsulfonyl)benzoyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-(4-Chlorobenzoyl)-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-(4-Cyanobenzoyl)-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-(4-Methoxybenzoyl)-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-(3-Methoxybenzoyl)-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-(5-Nitro-2-pyridinyl)-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-Methylsulfonyl-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans )-1-[(1-Methyl-4-imidazole)sulfonyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-(2-Thiophenesulfonyl)-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
(3R-trans)-1-(tert-Butylaminocarbonyl)-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide;
trans-1,1-Dimethylethyl3-[(hydroxyamino)carbonyl]-4-[[[4-[(4-quinolinyloxy)methyl]phenyl]amino]carbonyl]-1-pyrrolidinecarboxylate;
trans-N3-Hydroxy-N4-[4-[(4-quinolinyloxy)methyl]phenyl]-3,4-pyrrolidinedicarboxamidebis-;
trans-1,1-Dimethylethyl3-[[[4-[(2,6-dichloro-4-pyridinyl)methoxy]phenyl]amino]carbonyl]-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
trans-N3-[4-[(2,6-Dichloro-4-pyridinyl)methoxy]phenyl]-N4-hydroxy-3,4-pyrrolidinedicarboxamidebis-;
(2R-trans)-N2-[4-(4-quinolinyloxymethyl)phenyl]-N3-hydroxy-2,3-piperidinedicarboxamide;
(2R-trans)-1-methyl-N2-[4-(4-quinolinyloxymethyl)phenyl]-N3-hydroxy-2,3-piperidinedicarboxamide;
(2R-trans)-N2-[4-(2-methyl-4-quinolinylmethoxy)phenyl]-N3-hydroxy-2,3-piperidinedicarboxamide;
(2R-trans)-1-methyl-N2-[4-(2-methyl-4-quinolinylmethyloxy)phenyl]-N3-hydroxy-2,3-piperidinedicarboxamide;
(2R-trans)-1-ethyl-N2-[4-(2-methyl-4-quinolinylmethyloxy)phenyl]-N3-hydroxy-2,3-piperidinedicarboxamide;
(2R-trans)-1-cyclopropylmethyl-N2-[4-(2-methyl-4-quinolinylmethyloxy)phenyl]-N3-hydroxy-2,3-piperidinedicarboxamide;
(2R-trans)-1-(2-thiazolemethyl)-N2-[4-(2-methyl-4-quinolinylmethyloxy)phenyl]-N3-hydroxy-2,3-piperidinedicarboxamide;
(2R-trans)-1-Methyl-2-[[4-(2-methyl-4-quinolinylmethyloxy)piperidinyl]carbonyl]-3-(N-hydroxy)piperidinecarboxamide;
(2R-trans)-1-Methyl-2-[[4-(4-quinolinyloxymethyl)piperidinyl]carbonyl]-3-(N-hydroxy)piperidinecarboxamide;
(2R-trans)-1-Methyl-2-[[4-(2-methyl-4-quinolinyloxymethyl)piperidinyl]carbonyl]-3-(N-hydroxy)piperidinecarboxamide;
(2R-trans)-1-Methyl-2-[[4-(2-trifluoromethyl-4-quinolinyloxymethyl)piperidinyl]carbonyl]-3-(N-hydroxy)piperidinecarboxamide;
(2R-trans)-2-[(4-phenylpiperidinyl)carbonyl]-3-(N-hydroxy)piperidinecarboxamide;
(2R-trans)-1-Ethyl-2-[(4-phenylpiperidinyl)carbonyl]-3-(N-hydroxy)piperidinecarboxamide;
(2R-trans)-1-Methyl-2-[[4-(2-methoxyphenyl)piperidinyl]carbonyl]-3-(N-hydroxy)piperidinecarboxamide;
(2R-trans)-1-Methyl-2-[[4-(2-trifluoromethylphenyl)piperidinyl]carbonyl]-3-(N-hydroxy)piperidinecarboxamide;
(2R-trans)-1-Methyl-2-[[4-(2-methylphenyl)piperidinyl]carbonyl]-3-(N-hydroxy)piperidinecarboxamide;
(2R-trans)-1-Methyl-2-[[4-(3-methoxyphenyl)piperidinyl]carbonyl]-3-(N-hydroxy)piperidinecarboxamide; and,
(2R-trans)-1-Methyl-2-[[4-(3-trifluoromethylphenyl)piperidinyl]carbonyl]-3-(N-hydroxy)piperidinecarboxamide;
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides novel compounds of formula (I) for use in therapy.
In another embodiment, the present invention provides the use of novel compounds of formula (I) for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and C=N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring. The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl(or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl(or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl(or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemsxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroqinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. he pharmaceutically acceptable salts include the onventional non-toxic salts or the quaternary ammonium alts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a desired metalloprotease in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A series of five, six and seven membered ring heterocycles (B ring in formula I) can be constructed using the methods outlined in Schemes 1-10. (2S)-trans-2,3-Pyrrolidinedicarboxylate of formula 5 can be prepared using the procedures described in scheme 1. Alkylation of Cbz-protected L-aspartic acid 1 with allyl bromide using LDA followed by a chromatography to separate the two produced diastereomers yields the desired syn-diastereomer 2. An ozonolysis converts the vinyl 2 to an aldehyde 3. Hydrogenation leads to a ring closure to give a pyrrolidine 4. Derivatization at the nitrogen using an acid chloride, a chloroformate, a sulfonyl chloride or an aldehyde in the presence of NaBH3CN affords the pyrrolidine derivative 5. 
A series of (4S)-trans-2-oxo-4,5-pyrrolidinediccarboxylate of formula 9 can be prepared using the method shown in Scheme 2. Alkylation of Cbz-protected L-aspartic acid 1 with benzyl bromoacetate using LDA followed by a chromatography to separate the two produced diastereomers yields the desired syn-diastereomer 6. Hydrogenation removes the Cbz and benzyl groups. Cyclization using a coupling agent such as BOP produces a xcex3-lactam 8. Alkylation using an alkyl halide or an alkyl sulfonate gives the 2-oxopyrrolidine derivative 9. 
trans-3,4-Pyrrolidinedicarboxylate of formula 12 can be synthesized from a cycloaddition of fumarate 10 with an intermediate generated from reaction of paraformaldehyde and glycine followed by a derivatization at the nitrogen using an acid chloride, a chloroformate, a sulfonyl chloride or an aldehyde in the presence of NaBH3CN (Scheme 3). 
(2S)-trans-2,3-Piperidinedicarboxylate of formula 16 can be prepared starting with the intermediate 2 (Scheme 4). A hydroboration using 9-BBN converts the vinyl group to an alcohol 13 which is oxidized to give an aldehyde 14. Upon removal of the Cbz by hydrogenation, reductive amination between the released amine and the aldehyde took place, resulting in a ring closure to give the piperidine 15. Derivatization at the nitrogen using an acid chloride, a cholorformate, a sulfonyl chloride or an aldehyde in the presence of NaBH3CN affords the piperidine derivative 16. 
The synthesis of (5S)-trans-2-oxo-5,6-piperidinedicaroxylate of formula 20 can be prepared using the method depicted in Scheme 5. The alcohol intermediate 13 is oxidized to give a carboxylic acid 17. Hydrogenation to removed the Cbz followed by coupling using BOP yields the xcex4-lactam 19. Alkyation at the nitrogen with an alkyl halide or an alkyl sulfonate using NaH gives the xcex4-lactam derivative 20. 
The synthesis of (3S)-trans-3,4-piperidinedicarboxylate of formula 30 starts with a Cbz-protected xcex2-alanine 21 as shown in Scheme 6. Regioselective N-benzylation with benzyl bromide can be accomplished using NaH/THF. The acid 22 is coupled with the chiral auxiliary group (R)-4-phenylmethyl-2-oxazolidinone (HX) using pivaloyl chloride as the activating agent. Alkylation of 23 with tert-butyl bromoacetate using LDA produces the mono-substituted succinate 24. The chiral auxiliary group is removed using LiOH/H2O2 and the resulting acid is alkylated with allyl bromide using 2 equivalents of LDA to give the double-substituted succinate 26. The carboxylic acid is converted to a methyl ester 27 using iodomethane/DBU and the vinyl is converted to an aldehyde 28 by an ozonolysis. Hydrogenation results in a ring closure to give the piperidine 29 which is derived with an acid chloride, a chloroformate, a sulfonyl chloride or an aldehyde in the presence of NaBH3CN to give 30. 
The (4R)-trans-2-oxo-4,5-piperidinedicarboxylate of formula 34 can be prepared from the intermediate 28 (Scheme 7). The aldehyde in 28 is oxidized to give a carboxylic acid 31. Hydrogenation removes the Cbz and the N-benzyl groups. Cyclization is carried out using a coupling agent such as BOP and the xcex4-lactam is derived with an alkyl halide or an alkyl sulfonate to give 34. 
The (3S)-trans-3,4-homopiperidinedicarboxylate of formula 38 can be prepared starting from the intermediate 27. A hydroboration using 9-BBN converts the vinyl to an alcohol 35 which is oxidized to give an aldehyde 36. Hydrogenation produces the homopiperidine 37 which is derived with an acid chloride, a chloroformate, a sulfonyl chloride or an aldehyde in the presence of NaBH3CN to give 38. 
The synthesis of (5R)-trans-2-oxo-5,6-homopiperidinedicarboxylate of formula 42 starts with the alcohol intermediate 35 which is oxidized to give a carboxylic acid 39. Hydrogenation followed by cyclization using a coupling agent such as BOP yields the xcex5-caprolactam 41which is derived with an alkyl halide or an alkyl sulfonate to give 42. 
The synthesis of (6R)-trans-2-oxo-3,4-benzo-6,7-homopiperidinedicarboxylate of formula 47 is prepared as outlined in Scheme 10. Alkylation of 1 with benzyl 2-bromomethylbenzoate 43 using LDA followed by chromatography to separate the produced two diastereomers yields the aspartic acid derivative 44. Hydrogenation followed by cyclization using a coupling agent such as BOP produces the lactam 46 which is derived with an alkyl halide or an alkyl sulfonate to give 47. 
Alternatively, compoud of formula 30 where R is a benzyl and R3 is a benzyloxycarbonyl(Cbz) can be prepared using the method outlined in Scheme 11. The carboxylic acid 26 is converted to a benzyl ester 48 using benzyl bromide/K2CO3/DMF at an elevated temperature. An ozonolysis converts the vinyl to an aldehyde 49. Hydrogenation produces the piperidine ring 50. The amino is protected with a Cbz using N-benzyloxycarbonyloxysuccinimide (CbzOSu) and the carboxylic acid is converted to a benzyl ester using benzyl bromide/K2CO3/DMF at an elevated temperature to give 30 
Alternatively, compound of formula 30 where R7 is 9-fluorenylmethyl and R3 is 9-fluorenylmethoxycarbonyl(Fmoc) can be prepared using the method shown in Scheme 12. The piperidine 50 is reacted with FmocOSu to give Fmoc-protected intermediate 52. Coupling of the carboxylic acid 52 with 9-fluorenylmethanol using DCC in the presence of 4-dimethylaminopyridine yields compound 30. 
A series of R1 groups in formula I can be prepared using the methods outlined in Schemes 13-15. The 4-(aryloxyalkyl)aniline derivative of formula 58 is prepared starting from 4-(hydroxyalkyl)aniline 53 (Scheme 13). The amino is protected with a Boc to give 54. The alcohol of 54 is converted to a sulfonate 55. Displacement of 55 with an aryl or a heteroaryl alcohol 56 yields the ether intermediate 57 which is treated with 4 N HCl/dioxane to give 58. 
The 4-(aralkyloxy)aniline of formula 62 can be prepared using the method described in Scheme 14. Reaction of 4-tert-butoxycarbonylaminophenol 59, which was prepared from reaction of 4-aminophenol with di-tert-butyl-dicarbonate, with an aralkyl halide or sulfonate 60 yields the ether 61. Reduction of the nitro group using zinc or iron in acetic acid/water gives the aniline derivative 62. 
The diphenyl ether of formula 65 can be prepared using the method shown in Scheme 15. Reaction of 1-fluoro-4-nitrobenzene or its derivative 63 with an aryl or a heteroaryl alcohol 56 using cesium carbonate as base yields the diphenyl ether 64. Treatment with zinc in acetic acid/water reduces the nitro to an amine 65. 
A series of hydroxamate compounds of formulas 68, 72 and 76 can be prepared by assembling the B ring of formula 5, 9, 12, 16, 20, 30, 34, 38, 42, 47, or 66 with the R1 group of formula 58, 62, or 65 followed by conversion of a carboxylic acid to a hydroxamic acid using the methods outlined in Scheme 16-19. The hydroxamate of formula 68 can be prepared by condensation of a trans-1,2-cyclopentanedicarboxylic acid or trans-1,2-cyclohexanedicarboxylic acid with an aniline derivative 58, 62 or 65 followed by coupling of the carboxylic acid with a hydroxylamine hydrochloride using a coupling agent such as BOP (Scheme 16). 
The synthesis of the hydroxamate of formula 72 is shown in Scheme 17. The B ring of formula 5, 9, 12, 16, 20, 30, 34, 38, 42 or 47 where R7 is methyl, ethyl, benzyl or 9-fluorenylmethyl and R8 is tert-butyl is treated with TFA/CH2Cl2 to remove the tert-butyl. The resulting carboxylic acid is condensed with an aniline derivative of formula 58, 62 or 65 using a coupling agent such as BOP to give the amide 70. The methyl ester is saponified using sodium hydroxide and the resulting carboxylic acid 71 is converted to a hydroxamic acid 72. 
The hydroxamate of formula 76 is prepared using the method shown in Scheme 18. The B ring of formula 5, 9, 12, 16, 20, 30, 34, 38, 42 or 47 where R7 is methyl or ethyl and R8 is tert-butyl or benzyl is saponified to give a carboxylic acid 73. Coupling of 73 with an aniline derivative of formula 58, 62 or 65 using a coupling agent such as BOP yields the amide 74. Removal of the tert-butyl group using TFA or the benzyl group using hydrogenation followed by coupling with hydroxylamine hydrochloride using BOP affords the final product 76. 
Alternatively, compound 72 can be prepared using the procedures described in Scheme 19. The amide intermediate 70 where R7 is a benzyl or 9-fluorenylmethyl and R3 is benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl is subjected to a hydrogenation or treatment with piperidine in DMF to give 77. Reaction of 77 with an acid chloride, a chloroformate or an aldehyde in the presence of NaBH3CN produces 78 which is converted to a hydroxamic acid 72 by coupling with hydroxylamine hydrochloride using BOP. 
Alternatively, the B ring of formulas 83 and 86 where the ring structure is a 2,3-disubstituted pyrrolidine or piperidine can be prepared using the methods described in Schemes 20-21. L-Aspartic acid xcex2-tert-butyl ester 79 was alkylated with benzyl bromide to give the tris-benzylated aspartic acid derivative 80. Allylation of 80 with allyl bromide using LiHMDS provided the allylated derivative 81 as a mixture of 2 diastereomers which was subjected to an ozonolysis. Chromatography on a silica gel column of the aldehyde separated the two diastereomers. Hydrogenation of the syn-diastereomer 82 produced the pyrrolidine derivative 83. 
The olefin functionality of 81 was converted to an alcohol using 9-BBN. The two diastereomers of the alcohol were then separated using flash chromatography. The syn-diastereomer 84 was oxidized using an oxidizing agent such as pyridinium dichromate to give the aldehyde 85 which was subjected to hydrogenation to afford the piperidine derivative 86. 
The B ring of formula 83 or 86 was assembled with the Ri residue of formula 58, 62 or 65 using a coupling agent such as BOP. Reductive amination of 87 with an aldehyde using sodium cyanoborohydride produced N-alkylated derivative 88. Removal of the tert-butyl using acid followed by coupling with hydroxylamine hydrochloride using a coupling agent such as propyl chloroformate afforded the hydroxamic acid 90. 
Another type of R1 in formula I can be prepared using the methods described in Schemes 23-25. The N-Boc protected 4-hydroxypiperidine 91, which was prepared from reaction of 4-hydroxypiperidine with di-tert-butyl-dicarbonate, was alkylated with arylmethylhalide or arylmethyl sulfonate 92 to give the ether derivative 93. Deprotection of the Boc group using acid produced the unprotected piperidine derivative 94. 
N-Boc protected 4-hydroxymethylpiperidine 95, which was prepared from reaction of 4-hydroxymethylpiperidine with di-tert-butyl-di-carbonate, was converted to a sulfonate or halide 96. Displacement of the sulfonate or halide with phenol or its derivative, or quinolinol or its derivative produced the ether derivative 97 which was treated with acid to give the unprotected piperidine derivative 98. 
Another type of piperidine derivative 101 was prepared by coupling of 4-bromopyridine with a boronic acid 99 using Pd(PPh3)4 as catalyst followed by hydrogenation as shown in Scheme 25. 
A series of hydroxamic acids of formulas 104 and 107 can be prepared using the methods described in Schemes 26-27. Coupling of the B ring of formula 69 with the R1 residue of formula 94, 98 or 101 using a coupling agent such as BOP produced the carboxamide derivative 102. Saponification of the ester produced the the acid 103 which was converted to the hydroxamic acid 103 by coupling with hydroxylamine hydrochloride using a coupling agent such as n-propyl chloroformate. 
Coupling of the B ring of formula 73 with the R1 residue of formula 94, 98 or 101 using a coupling agent such as BOP produced the carboxamide 105 which was subjected to treatment using an acid such as TFA or hydrogenation to remove the R8 group. Coupling of carboxylic acid 106 with hydroxylamine hydrochloride using coupling agent such as isobutyl chloroformate produced the hydroxamic acid 107. 
Alternatively, the hydroxamic acids of formula 111, where the B ring is a 2,3-disubstituted pyrrolidine or piperidine, can be prepared using the method described in Scheme 28. Coupling of the B ring of the formula 83 or 86 with the R1 residue of the formula 94, 98 or 101 produced the carboxamide derivative 108. Reductive amination at the pyrrolidine or piperidine nitrogen using an aldehyde in the presence of sodium cyanoborohydride produced the N-alkyl derivative 109 which was treated with an acid to remove the tert-butyl group. The carboxylic acid 110 was converted to the hydroxamic acid 111 in a manner as described previously. 
One diastereomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940).